Research explores molecular mechanisms connecting TBI to Alzheimer’s

Each year, approximately 2.5 million people suffer from traumatic brain injury (TBI), often increasing their risk of developing Alzheimer’s disease later in life.

Researchers led by The Ohio State University Wexner Medical Center and College of Medicine used mouse models and human postmortem brain tissue to study the molecular underpinnings that could increase the risk of Alzheimer’s disease after TBI.

Due to the prevalence of both TBI and Alzheimer’s disease in humans, understanding the molecular mechanism underlying the transition from TBI to Alzheimer’s disease is critical to developing future therapies that reduce this risk.”

Hongjun “Harry” Fu, PhD, senior author of the study, assistant professor of neuroscience, Ohio State University

Research results are published online in the journal Acta Neuropathologica.

Researchers found that TBI increases hyperphosphorylated tau, astro- and microgliosis, synaptic dysfunction and cognitive impairment associated with the development of Alzheimer’s disease. Furthermore, they found that downregulation of BAG3, a protein involved in protein clearance via the autophagy-lysosome pathway, contributes to the accumulation of hyperphosphorylated tau in neurons and oligodendrocytes after traumatic brain injury in the mouse models and human post-mortem brain tissue with history from TBI.

Using an AAV-based approach to BAG3 overexpression in neurons, they found that BAG3 overexpression improves tau hyperphosphorylation, synaptic dysfunction, and cognitive deficits, likely through the potentiation of the autophagy-lysosome pathway.

“Based on our findings, we believe that targeting neuronal BAG3 may be a therapeutic strategy for preventing or reducing Alzheimer’s disease-like pathology,” said first author Nicholas Sweeney, a research associate in neuroscience in the state of Ohio.

This work builds on their previous research that had identified BAG3 as a central gene regulating tau homeostasis from non-diseased human postmortem tissue. Therefore, BAG3 may be a contributing factor to the cellular and regional vulnerability to tau pathology in AD, said co-first author Tae Yeon Kim, a PhD student from Ohio State’s Biomedical Sciences Graduate Program.

“Since previous research using human tissue and mouse models shows that tau pathology increases after traumatic brain injury, we wondered whether BAG3 could be a factor contributing to the accumulation of tau after traumatic brain injury,” Fu said. “Indeed, we found that BAG3 dysfunction contributes to disruption of protein clearance mechanisms, resulting in tau accumulation in mouse models and in human post-mortem tissue with TBI and Alzheimer’s disease.”

Future research will attempt to validate the relationship between TBI, BAG3, tau pathology, gliosis, and neurodegeneration using a new model of TBI. Known as the Closed Head Induced Model of Engineered Rotational Acceleration (CHIMERA), this model mimics the most common mild TBI conditions in humans, Fu said.

“Completion of future studies will allow us to better understand how TBI and Alzheimer’s disease are biologically linked and develop new therapies that may reduce the risk of developing Alzheimer’s disease after TBI,” Fu said .

The research team included scientists from Ohio State, Arizona, New York, West Virginia and Japan.

This work was supported by the Department of Defense, the National Institute on Aging of the National Institutes of Health, the Seed Grant from the Neurological Research Institute of The Ohio State University, and the Summer Undergraduate Research Fellowship from the Ohio State University Chronic Brain Injury Discovery Theme .